RESUMO
[reaction: see text] Alkyl azides react with saturated ketones upon treatment with Lewis acids to afford ring-expansion products through the azido-Schmidt reaction, but this reaction does not proceed when alpha,beta-unsaturated ketones are used. In this study, alkyl azides were reacted with enones in the presence of Lewis acids to give enaminones (vinylogous amides), which formally involve a ring contraction reaction. The mechanism and scope of this reaction is discussed.
Assuntos
Ácidos/química , Azidas/química , Azidas/síntese química , Catálise , Cetonas/química , Modelos Químicos , Estrutura MolecularRESUMO
A series of tetrahydropyranyl (THP) derivatives has been developed as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT) for use as anticancer agents. Structural modification of the submicromolar hit compound 3 led to the potent 3-methoxy substituted analogue 27. Further SAR development around the THP ring resulted in an additional 10-fold increase in potency, exemplified by analogue 75 with an IC(50) of 1.3 nM. Active and potent compounds demonstrated a dose-dependent increase in Ras cytosolic protein. Potent ICMT inhibitors also reduced cell viability in several cancer cell lines with growth inhibition (GI(50)) values ranging from 0.3 to >100 µM. However, none of the cellular effects observed using ICMT inhibitors were as pronounced as those resulting from a farnesyltransferase inhibitor.
Assuntos
Antineoplásicos/síntese química , Proteínas Metiltransferases/antagonistas & inibidores , Piranos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Citosol/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Técnicas de Inativação de Genes , Humanos , Proteínas Metiltransferases/genética , Piranos/química , Piranos/farmacologia , Proteínas Recombinantes/química , Estereoisomerismo , Relação Estrutura-Atividade , Proteínas ras/biossínteseRESUMO
We have shown previously that the target of the potent cytotoxic agent 4-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino]-N-(3-pyridylmethyl)benzamide (CB38065, 1) is nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known we sought to optimize the biochemical and cellular Nampt activity of 1 as well as its cytotoxicity. It was found that a 3-pyridylmethylamide substituent in the A region was critical to cellular Nampt activity and cytotoxicity, although other aromatic substitution did yield compounds with submicromolar enzymatic inhibition. Small unsaturated groups worked best in the D-region of the molecule, with 3,3-dimethylallyl providing optimal potency. The E region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for activity, and many substituents were tolerated at C² of the quinazolin-4-one. The best compounds showed subnanomolar inhibition of Nampt and low nanomolar cytotoxicity in cellular assays.
Assuntos
Antineoplásicos/síntese química , Benzamidas/síntese química , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Quinazolinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Modelos Moleculares , Quinazolinas/química , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Concise and asymmetric total synthesis of the title compounds are described. The key ring system was constructed using an intramolecular Schmidt reaction on a norbornenone derivative, which was subsequently subjected to ring-opening metathesis followed by reduction. An unusual isomerization of the C-6 ethyl group afforded the desired stereochemistry of the natural product. The synthesis is readily adaptable to analogue production.
Assuntos
Alcaloides/síntese química , Indolizidinas/síntese química , Lactamas/síntese química , Indolizidinas/química , Estrutura Molecular , EstereoisomerismoRESUMO
During investigations of cyclization reactions between chiral allylsilanes and N-acyliminium ions, it was discovered that a suitably positioned benzyloxy group on the allylsilane component caused a reversal in the diastereoselectivity of these reactions relative to that normally observed with alkyl-substituted allylsilanes. This effect was subsequently observed in two other reaction types. Investigations into this effect led to the proposal of product formation through thermodynamic control facilitated by neighboring group interactions with a transient cationic species. This hypothesis was experimentally supported by the isolation of an intermediate in the proposed mechanistic pathway.